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ABSTRACT: Degeneration and regeneration of nerves in skin flaps has so far been studied mainly by classical staining methods and there is little information on neuropeptide involvement. Therefore, we have investigated immunocytochemically the temporal course of reinnervation of neuropeptide appearance in skin flaps of mice. Fibres immunoreactive for a general neural marker protein gene product 9.5 (PGP 9.5), and for the neuropeptides substance P, calcitonin gene-related peptide (CGRP), vasoactive intestinal peptide (VIP) and neuropeptide Y (NPY) disappeared by 24 h in the flap and surrounding skin. By the 7th day, PGP 9.5-immunoreactive nerves were seen close to the pedicle. By 15 days, they were seen within the body of the flap, clustered focally without specific organisation in greater density than in control skin. Many were also immunoreactive for CGRP and substance P. Neural immunoreactivity for VIP and NPY appeared later (day 30). Thus, regrowing nerves appear initially to be denser than normal innervation. The early appearance of apparently hypertrophic sensory neuropeptide-containing (CGRP and substance P) fibres may have a role in trophic, regulatory and reparative processes.